Sep 2, 2007

2007 Week 36: Erythritol toxicity

Sugar diseases are a problem for ferrets - particularly insulinoma - and we are always looking for safe sweeteners to help the medicine go down easier. (Frankly, I got tired of pink Pepto Bismol baths pretty quickly.)

Erythritol is under consideration as it is widely available in Japan. But as it is a sugar alcohol like xylitol, it raises some questions of toxicity.

Here are some papers from PubMed regarding its effects after testing on dogs, rats, mice, and rabbits.

"Chronic (1-year) oral toxicity study of erythritol in dogs."Highlights from the abstract:-> There were no clinically relevant changes in hematological or clinicochemical parameters attributable to treatment.-> ...however, the available data did not indicate treatment-related effects on the urinary excretion of electrolytes (K+, Na+, Mg2+, and Pi) or enzymes (gamma-glutamyltranspeptidase, N-acetyl glucosaminidase, and lactate dehydrogenase-> Quantitation of erythritol in the urine demonstrated that 50 to 80% of the ingested dose was absorbed and excreted in the urine.-> It was concluded that daily erythritol consumption of up to 3.5 g/kg body wt was well tolerated by dogs.

"Four-week oral toxicity study with erythritol in rats."Highlights from the abstract:->Soft stools and diarrhea were observed in male and female animals of the 10% group and in female animals of the 5% group. These symptoms disappeared during the course of the study.->Small statistically significant changes in certain hematological, clinical chemistry, and urine parameters were noted in the high-dose group but were judged not to be biologically important.->Based on these results, it was concluded that the feeding of erythritol at a dietary level of 10% did not result in toxicologically significant effects.

"Subchronic oral toxicity studies with erythritol in mice and rats."Highlights from the abstract:->There were no treatment-related mortalities in either mice or rats.->Hematological and clinicochemical examinations of blood and plasma did not reveal any treatment-related effects.->Urine output increased with increasing erythritol dose.->Increased relative and absolute kidney weights were observed in both sexes of mice in the 20% erythritol group, in male mice of the 5 and 10% groups, and in rats of the 10 and 20% erythritol groups.->In rats, the creatinine-normalized urinary excretion of GGT, NAG, and some electrolytes (Na+, K+, and Ca2+) was increased in some erythritol groups but a clear dose-response relationship was evident only for calcium.->In particular, the morphological integrity of the kidneys was not adversely affected by the treatment in either species. The increases in urinary excretion of protein, GGT, NAG, and electrolytes were considered to result from extensive osmotic diuresis and a potential overload of the renal excretory system at the high dose levels employed.

"Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data."Highlights from the abstract:->The majority of the safety studies conducted were feeding studies in which erythritol was mixed into the diet at concentrations as high as 20%->The metabolic studies in animals have shown that erythritol is almost completely absorbed, not metabolized systemically and is excreted unchanged in the urine.->The safety studies have demonstrated that erythritol is well tolerated and elicits no toxicological effects.->Erythritol administered orally to humans was rapidly absorbed from the gastrointestinal tract and quantitatively excreted in the urine without undergoing metabolic change.

"Chronic toxicity and carcinogenicity study of erythritol in rats."Highlights from the abstract:->All treatments were well tolerated without diarrhea or other side effects.->Hematological and clinicochemical examinations did not reveal noticeable changes which could be attributed to treatment.->urine samples collected during five 48-hr periods ... showed that about 60% of ingested erythritol was excreted unchanged. The urine volumes increased with increasing dietary erythritol levels.->Except for more frequent pelvic nephrocalcinosis (precipitation of calcium phosphate in the renal tubules, with resultant renal insufficiency.)in female rats of all erythritol dose groups, the histopathological examinations did not reveal any nonneoplastic, preneoplastic, or neoplastic changes that could be attributed->In the absence of morphological alterations in the kidneys or other signs of nephrotoxicity, the increased excretions of NAG, GGT, LMP, and TP are regarded as innocuous, functional sequelae of the renal elimination of erythritol.->Except for nephrocalcinosis, which is commonly seen in polyol-fed rats, no other treatment-related, morphological changes were observed in the kidneys. Evidence for a tumor-inducing or tumor-promoting effect of erythritol was not seen.

"Embryotoxicity and teratogenicity study with erythritol in rats."Highlights from the abstract:->The treatment was generally well tolerated and no mortality occurred in any group.->Examination of the fetuses for external, visceral, and skeletal alterations did not reveal any fetotoxic, embryotoxic, or teratogenic effects.->In conclusion, no adverse effects were observed at erythritol doses of up to about 6.6 g/kg body wt/day, i.e., the highest dose tested.

"Teratology study of erythritol in rabbits."Highlights from the abstract:->Maternal effects (auricular edema, and bradypragia) were observed in the high-dose group.->No deaths or significant abnormalities occurred in animals given 1.0 or 2.24 g/kg->No effect was observed in the reproductive performance of the dams or in fetal development from ingestion at any of the treatment levels.

One thing often mentioned in the studies is that there were noticable changes (enlargements, weight increases) to the 'cecum'. As ferrets do not have one, I did not list it with the other highlights.

If you read the abstracts with dosing details you will also notice that testing was done a rather high levels. I would think from these that it is _possible_ to safely use erythritol in healthy ferrets especially in the under 1gm/kg range that I am considering. However, there are certain drugs that cause increases or decreases in K or other electrolyte uptake. That is something to consider before using erythritol as a sweetener for medicine .